ABSTRACT The most effective measure for the prevention of influenza virus infection is vaccination. However, due to ongoing antigenic drift, current influenza vaccines need annual reformulation to provide sufficient protection. Furthermore, immune responses elicited upon influenza vaccination are strain-specific and fail to provide protection against novel seasonal and pandemic viruses, necessitating the development of a universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains. A major target for the development of protective immunity against influenza is the hemagglutinin glycoprotein (HA), which comprises two distinct functional domains: the globular head, which participates in viral entry and is subject to antigenic drift, and the stalk domain, which is highly conserved and mediates viral fusion. Immunodominant antigenic sites on the HA head elicit high-affinity, strain-specific anti-HA Ab responses, whereas in contrast, Abs against conserved epitopes can mediate broadly protective activity, but are immunosubdominant. To overcome the inherent immunodominance of the HA head and refocus immunity towards conserved, cross-protective epitopes, we will engineer innovative mosaic HA protein immunogens in which HA head antigenic sites will be silenced. Our prior research demonstrated that vaccination with HA:anti-HA IgG immune complexes (ICs) can modulate adaptive immunity through specific interactions of the Fc domain of the IgG with Fc? receptors (Fc?R) on the surface of effector leukocytes. Our in-depth studies revealed that engagement of specific Fc?Rs: CD23 on B-cells and Fc?RIIa on dendritic cells (DCs), is critical for the induction of high-affinity IgG responses and T-cell immunity, respectively. Based on this knowledge, we will exploit these pathways to broaden specificity, increase affinity and select for long-lived humoral and cellular immunity to conserved influenza epitopes. We will design and evaluate the immunogenicity of IC-based immunogens comprising mosaic HAs and Fc-engineered anti-HA IgGs with selective affinity for specific human Fc?R types. These studies will lead to the development and pre-clinical evaluation of vaccination strategies to elicit robust and long-lasting antiviral immunity, which could improve the breadth of current seasonal vaccines, but could also be employed in the development of novel, next-generation universal influenza virus vaccines.